We propose to investigate whether selected gene-environment interactions are risk factors for primary open angle glaucoma (POAG) in two prospectively followed cohorts of men and women. First, we will determine whether several variants of the endothelial nitric oxide synthase gene (NOS3) are associated with POAG using a nested case-control cohort drawn from our study population. Then, in separate cohort analyses we will study hormone replacement therapy and alcohol consumption in relation to POAG using stratified and multivariate techniques after controlling for important confounders. Finally, we will return to our case-control cohort to ascertain how the interaction between selected NOS3 polymorphisms and our environment exposure alters the risk of developing POAG. The Nurses' Health Study (NHS) began in 1976 among 121,700 women ranging in age from 30 to 55. Approximately 89,000 participants completed a validated semi quantitative food frequency questionnaire (FFQ) in 1980 and every 2-4 years since. The Health Professionals Follow-up Study (HPFS) began in 1986 among 52,000 men ranging in age from 45-75, all of whom completed a FFQ at baseline and every 4 years thereafter. Both groups have been sent a questionnaire biennially to update exposure information and report major illness including POAG. Information has been collected repeatedly on postmenopausal hormone use, alcohol consumption and other related covariates. We have 69,099 DNA samples from NHS participants and 33,545 DNA samples from HPFS participants in storage. In the proposed study we will confirm reports of POAG by contacting the participant's eye care provider, and obtaining pertinent information from the medical record. A self-report of POAG, will be confirmed by systematic record review documenting reproducible visual field loss consistent with glaucomatous optic neuropathy. We anticipate identifying 1246 POAG cases, 909 of which will have DNA samples available for analysis. Overall, the prospective design, large size of the cohorts, the high follow-up rates, repeated assessment of exposures known to alter NOS3 gene activity, and carefully confirmed POAG definition provide a unique opportunity to evaluate several hypotheses of public health importance. The discovery of gene-environment interactions that serve as determinants of POAG could lead to genotype-specific primary prevention strategies for this complex disease.